1. AMPK modulation ameliorates dominant disease phenotypes of CTRP5 variant in retinal degeneration
- Author
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Miyagishima, Kiyoharu J, Sharma, Ruchi, Nimmagadda, Malika, Clore-Gronenborn, Katharina, Qureshy, Zoya, Ortolan, Davide, Bose, Devika, Farnoodian, Mitra, Zhang, Congxiao, Fausey, Andrew, Sergeev, Yuri V, Abu-Asab, Mones, Jun, Bokkyoo, Do, Khanh V, Kautzman Guerin, Marie-Audrey, Calandria, Jorgelina, George, Aman, Guan, Bin, Wan, Qin, Sharp, Rachel C, Cukras, Catherine, Sieving, Paul A, Hufnagel, Robert B, Bazan, Nicolas G, Boesze-Battaglia, Kathleen, Miller, Sheldon, and Bharti, Kapil
- Subjects
Macular Degeneration ,Stem Cell Research - Induced Pluripotent Stem Cell - Human ,Neurosciences ,Stem Cell Research ,Eye Disease and Disorders of Vision ,Stem Cell Research - Induced Pluripotent Stem Cell ,Neurodegenerative ,Genetics ,2.1 Biological and endogenous factors ,Aetiology ,Eye ,AMP-Activated Protein Kinases ,Female ,Humans ,Male ,Middle Aged ,Phenotype ,Retinal Degeneration - Abstract
Late-onset retinal degeneration (L-ORD) is an autosomal dominant disorder caused by a missense substitution in CTRP5. Distinctive clinical features include sub-retinal pigment epithelium (RPE) deposits, choroidal neovascularization, and RPE atrophy. In induced pluripotent stem cells-derived RPE from L-ORD patients (L-ORD-iRPE), we show that the dominant pathogenic CTRP5 variant leads to reduced CTRP5 secretion. In silico modeling suggests lower binding of mutant CTRP5 to adiponectin receptor 1 (ADIPOR1). Downstream of ADIPOR1 sustained activation of AMPK renders it insensitive to changes in AMP/ATP ratio resulting in defective lipid metabolism, reduced Neuroprotectin D1(NPD1) secretion, lower mitochondrial respiration, and reduced ATP production. These metabolic defects result in accumulation of sub-RPE deposits and leave L-ORD-iRPE susceptible to dedifferentiation. Gene augmentation of L-ORD-iRPE with WT CTRP5 or modulation of AMPK, by metformin, re-sensitize L-ORD-iRPE to changes in cellular energy status alleviating the disease cellular phenotypes. Our data suggests a mechanism for the dominant behavior of CTRP5 mutation and provides potential treatment strategies for L-ORD patients.
- Published
- 2021